Regulation of Transgene Derived SSAT Gene Expression

Overexpression of SSAT in transgenic rodents not only offers means to study the phenotypical consequences of activated polyamine catabolism, it also offers opportunities to elucidate the regulation of SSAT gene expression. Tissues of transgenic animals overexpressing SSAT typically accumulate large amounts SSAT-specific messenger RNA (mRNA), yet the SSAT activity and immunoreactive protein are mostly only marginally elevated (7,10). This suggests that SSAT gene expression is under extremely strict temporal control that is likely to occur at some posttranscriptional level. SSAT is known to be powerfully induced by the higher polyamines and especially by their N-alkylated analogs (6). An immense (up to 40,000-fold) hepatic stimulation of SSAT

Fig. 1. The polyamine cycle. AdoMetDC, S-adenosylmethionine decarboxylase; Spm, spermine; PAO, polyamine oxidase; SSAT, spermidine/spermine W'-acetyltransferase; ODC, ornithine decarboxylase; DFMO, 2-difluoromethylomithine. The numbers indicate adenosine triphosphate equivalents consumed.

activity was induced by treating transgenic mice overexpressing SSAT transgene under the control of mouse metallothionein I promoter with A^A^-diethylnorspermine (DENSPM) (11). The latter induction most likely occurred at a level of gene expression downstream of mRNA accumulation, as the transgene was driven by a heterolo-gous promoter not supposed to be induced by polyamine analogs. Some recent evidence indicates that alternative splicing of pre-mRNA may be involved in the regulation of SSATgene expression (12,13). Our unpublished findings have likewise indicated that polyamine analogs influence the splicing of SSAT pre-mRNA. As expected, transgenic mice overexpressing SSAT and fetal fibroblasts derived from them are much more sensitive to the toxic action exerted by polyamine analogs (10,14).

Overexpression of SSAT in transgenic rodents not only disturbs tissue polyamine homeostasis, but also creates a complex phenotype affecting skin, white fat depots, female fertility, liver, pancreas, central nervous system, and the lifespan of the animals.

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